The past quarter century has witnessed a dramatic increase in the prevalence in subjects of a cluster of inter-related metabolic disease states, primarily caused by obesity and immune disease states, jeopardizing homeostasis and leading to the diabetic state. The incidence of diabetes, with or without obesity, has reached epidemic proportions, bringing with it impaired quality of life and life span due to serious clinical co-morbidities such as peripheral vascular and neuropathic disease, with or without pain, ulcerative skin lesions often leading to infection, gangrene, and amputation, vision loss, cardiac and renal failure and brain disorders. Without question, chronic disease associated with diabetes represents a heavy and growing burden to society in terms of both direct healthcare costs that have reached catastrophic levels and mortality rates (American Health Rankings, 2010 edition).
According to American Diabetes Association, as of 2010, 23.6 million children and adults, approximately 8% of population in the United States (US) have diabetes, and over 57 million people are clinically considered pre-diabetic in the US. According to United HealthCare, based on current trends, 52% of the US adult population could have pre-diabetes or diabetes by 2020—up from an estimated 40% in 2010, resulting in costs estimated at $3.4 trillion for diabetes-related care over the decade from 2010 to 2020. The incidence of adolescent type 2 diabetes (T2D) has increased 10 fold from 1982 to 1994 (Pinhas-Hamiel 1996). Over 25% of obese children are considered glucose intolerant. Insulin resistance is related to inflammation and obesity induces a state of chronic inflammation. In obese states, adipose tissue secretes inflammatory agents such as cytokines Adipose tissue macrophages alter insulin sensitivity in animal models. Obesity can be reframed as an inflammatory disease, with macrophages acting at the junction between over nutrition and inflammation.
Insulin is a peptide hormone produced by beta cells (β-cells) within the islets of Langerhans in the endocrine pancreas. Insulin promotes glucose utilization, protein synthesis, and the formation and storage of neutral lipids. Insulin is generally required for the entry of glucose into muscle. Glucose stimulates both the secretion and biosynthesis of insulin. Basal insulin secretion is normally generated to synthesize glycogen from glucose in the absence of glucose-stimulated insulin secretion.
Insulin and related insulin-like growth factors (IGF-1) give trophic support to neural tissue; their receptors are present on vanilloid transient receptor potential 1 (TRPV1) neurons, which are essential in serving to maintain neural vitality and to promoting regeneration of small sensory nerve fibers (Migdalis 1995; Sathianathan 2003; VanBuren 2005). Moreover, TRPV1 sensory neurons appear to be down regulated in pre- and post-diabetic states whereby they may fail to influence the appropriate release of calcitonin gene-related peptide (CGRP) and other neuropeptides that influence production of insulin from the beta cell (Okabayashi 1989). Reports of preclinical and clinical experiments state that exogenous administration of CGRP or induction of the endogenous release of CGRP from TRPV1 sensory neurons by the application of a TRPV1 antagonist results in the following relevant biological responses: (1) pain signals conveyed to the central nervous system (CNS); (2) a neurogenic inflammatory response consisting of vasodilatation and edema formation, the latter not pronounced in humans; (3) insulin secretion at appropriate concentrations and (4) immunosuppression (Nagy 2004, Brain and Grant 2004; Razavi 2006). In animal models of Type I diabetes (T1D) with insulinopenia, targeted expression of CGRP to β-cells or local intra-arterial administration of substance P (SP), which is co-localized with CGRP in TRPV1 sensory neurons but not as prevalent, has been reported to prevent or ameliorate diabetes (Khachatryan 1997; Razavi 2006).
In addition to T1D, β-cell dysfunction with impaired insulin regulation is also observed in subjects in the early stages of diabetes development, including impaired glucose tolerance (IGT) and obesity-related hyperinsulinemia. In obese animals, capsaicin-sensitive C-fibers containing TRPV1 sensory neurons are markedly impaired, suggesting that intra-pancreatic neuronal release of CGRP is reduced, which would further amplify β-cell dysfunction particularly if the pancreas is maladapted to high levels of insulin (Ahren 2009). Paradoxically, the deletion or degeneration of TRPV1 sensory neurons innervating the pancreas has been reported to result in improved glucose homeostasis and insulin production (Razavi 2006; Gram 2007).
Impaired CGRP release due to TRPV1 sensory neuron pathology and/or abnormal interaction in the pathway featuring insulin production and the feedback function of the insulin receptor exhibit an inflammatory (e.g. autoimmune) state and are seen in T1D. It has been reported that increased concentrations of CGRP and other neuropeptides can prevent T1D in experimental animal models (Khachatryan 1997).
The release of CGRP to the β-cell has been reported to improve glucose and insulin homeostasis (see Gram 2005, 2007). Animal experiments have reported that sensory nerve dysfunction may contribute to hyperinsulinism, pre-diabetes initiation and progression of diabetes (Carillo 2005; Leighton and Foot 1995). Reports indicate that an imbalance in the insulin feedback control system may be “normalized” through enhancing the local supply of sufficient neuropeptides, including CGRP (Razavi 2006, Khachatryan 1997). Ablation and administration of TRPV1 antagonists have been reported to improve glucose and insulin homeostasis in subjects with pre-diabetes or T2D. See Dosch et al., U.S. patent application Ser. No. 12/478,898, incorporated by reference in its entirety.
TRPV1 sensory neurons have been shown to act as a central controller of both β-cell stress and T cell infiltration (Dosch et. al). Elimination of neurons containing TRPV1 by capsaicin or resiniferatoxin (RTX) or transection of sensory nerves innervating the pancreas and functional normalization of TRPV1 sensory neurons has the same net islet-specific outcomes: prevention of diabetes, improved glucose/insulin homeostasis, normalized insulin sensitivity and abrogation of insulitis or T1D (Szallasi 1999).
Systemic delivery of pharmaceutical agents has been the typical treatment for β-cell dysfunction and the hyperglycemia associated with diabetes; nevertheless, this approach can have limited dosing and compliance issues, and serious side effects. While non-insulin and insulin pharmacotherapies have been the hallmark in controlling hyperglycemia, there are no therapies that induce immunosuppression, and prevent/attenuate diabetes without significant risk.